This invention relates to a series of phenylalanine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T. A. Nature, 346 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin xcex1 chains and 8 different integrin xcex2 chains have been identified [Sonnenberg, A Current Topics in Microbiology and Immunology, 18, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed xcex14xcex27 consists of the integrin xcex14 chain associated with the integrin xcex21 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin xcex1 and xcex2 chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognized [Sonnenberg, A., ibid.].
The importance of cell adhesion molecules in human leukocyte function has been further highlighted by a genetic deficiency disease called Leukocyte Adhesion Deficiency (LAD) in which one of the families of leukocyte integrins is not expressed [Marlin, S. D. et al., Exp. Med. 164, 855 (1986)]. Patients with this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal.
The potential to modify adhesion molecule function in such a way as to beneficially modulate immune and inflammatory responses has been extensively investigated in animal models using specific monoclonal antibodies that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al., Am. J. Physiol. 263, L723, (1992); Binns, R. M. et al., J. Immunol. 157, 4094, (1996)]. A number of monoclonal antibodies which block adhesion molecule function are currently being investigated for their therapeutic potential in human disease.
One particular integrin subgroup of interest involves the xcex14 chain which can pair with two different xcex2 chains xcex21 and xcex27 [Sonnenberg, A. ibid]. The xcex14xcex21 pairing occurs on many circulating leukocytes (for example, lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils. xcex14xcex21 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J., et al., Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between xcex14xcex21 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A, et al., Nature, 356, 63, (1992); Podolsky, D. K., et al., J. Clin. Invest. 92, 373, (1993); Abraham, W. M., et al., J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of xcex14 and xcex27 has been termed LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like xcex14xcex21, binds to VCAM-1 and fibronectin. In addition, xcex14xcex27 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al., Cell, 74, 185, (1993)]. The interaction between xcex14xcex27 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D. et al., PNAS, 91, 12604 (1994)].
Regions of the peptide sequence recognized by xcex14xcex21 and xcex14xcex27 when they bind to their ligands have been identified. xcex14xcex21 seems to recognize LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al., ibid] while xcex14xcex27 recognizes a LDT sequence in MAdCAM-1 [Briskin, M. J. et al., J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al., J. Biol. Chem. 269, 18668, (1994); Shroff, H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice, P. J. Immunol. 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the xcex14xcex21 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitized mouse [Ferguson, T. A. et al., PNAS 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
This invention is directed to a group of compounds which are potent and selective inhibitors of xcex14 integrins. Members of the group are able to inhibit xcex14 integrins such as xcex14xcex21 and/or xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on a integrins of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (I): 
wherein
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, or R1 and R2, together with the nitrogen atom to which they are attached, are joined to form an optionally substituted heterocyclic ring provided that said substituted alkyl, substituted alkenyl and substituted cycloalkyl do not carry an aryl, substituted aryl, heteroaryl or substituted heteroaryl group;
R4 and R5 are independently selected from the group consisting of xe2x80x94L2(Alk3)tL3(R7)u in which L2 and L3 are independently a covalent bond or a linker atom or group, t is zero or the integer 1, u is an integer 1, 2, or 3, Alk3 is an aliphatic or heteroaliphatic chain and R7 is hydrogen or halogen atom or a group selected from alkyl, xe2x80x94OR8 [where R8 is a hydrogen atom or an optionally substituted alkyl group], xe2x80x94SR8, xe2x80x94NR8R9 [where R8 is a hydrogen atom or an optionally substituted alkyl group], xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R8, xe2x80x94SO3H, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94OCO2R8, xe2x80x94CONR8R9, xe2x80x94CSNR8R9, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94N(R8)COR9, xe2x80x94N(R8)CSR9, xe2x80x94SO2N(R8)(R9), xe2x80x94N(R8)SO2R9, xe2x80x94N(R8)CON(R9)(R10), [where R10 is a hydrogen atom or an optionally substituted alkyl group], xe2x80x94N(R8)CSN(R9)(R10) or xe2x80x94N(R8)SO2N(R9)(R10);
Alk2 is a straight or branched alkylene chain;
m is zero or an integer 1;
R6 is a hydrogen atom or a methyl group;
R is a carboxylic acid (xe2x80x94CO2H) or a derivative thereof,
Ra is a hydrogen or a methyl group;
Ar is an optionally substituted aromatic or heteroaromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
One preferred group of compounds of this invention include compounds of formula (2): 
wherein R, Ra, R1, R2, R6, Alk2, m and Ar are as defined above and the salts, solvates, hydrates and N-oxides thereof.
Another class of compounds of this invention is where Ar is selected from the group consisting of moieties of formula IIIa, IIIc, IIId, IIe or IIIf: 
wherein
R5xe2x80x2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6xe2x80x2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10xe2x80x2 where R10xe2x80x2 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R7xe2x80x2 and R8xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16xe2x80x2 and R17xe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18xe2x80x2 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20xe2x80x2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21xe2x80x2 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2;
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
It will be appreciated that compounds of formula (I) and (II) may have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formulae (I) and (II) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds of formulae (1) and (2), derivatives of the carboxylic acid group, R, include carboxylic acid esters and amides. Particular esters and amides include xe2x80x94CO2Alk5 and xe2x80x94CONR5R9 groups as described herein.
Alk2 in the compounds of the invention may be for example a straight or branched C1-3 alkylene chain. Particular examples include xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 and xe2x80x94(CH2)2xe2x80x94.
When in the compounds of formula (1), L2 and/or L3 is present as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94; xe2x80x94OC(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NR11xe2x80x94 [where R11 is a hydrogen atom or an optionally substituted alkyl group], xe2x80x94CON(R11)xe2x80x94, xe2x80x94OC(O)N(R11)xe2x80x94, xe2x80x94CSN(R11)xe2x80x94, xe2x80x94N(R11)COxe2x80x94, xe2x80x94N(R11)C(O)Oxe2x80x94, xe2x80x94N(R11)CSxe2x80x94, xe2x80x94S(O)2N(R11)xe2x80x94, xe2x80x94N(R11)S(O)2xe2x80x94, xe2x80x94N(R11)CON(R11)xe2x80x94, xe2x80x94N(R11)CSN(R11xe2x80x94, or xe2x80x94N(R11)SO2N(R11)xe2x80x94 groups. Where the linker group contains two R11 substituents, these may be the same or different.
When R7, R8, R9, R10 and/or R11 in the compounds of formula (1) is an alkyl group it may be a straight or branched C1-6 alkyl group, e.g. a C1-3 alkyl group such as a methyl or ethyl group. Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C1-6 alkoxy e.g. methoxy or ethoxy groups.
When Alk3 is present in the compounds of formula (1) as an aliphatic or heteroaliphatic chain it may be for example any of C-C10 aliphatic or heteroaliphatic chains.
When Alk3 is present in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched chain C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl chains.
Heteroaliphatic chains represented by Alk3 include the aliphatic chains just described but with each chain additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L4 where L4 is as defined above for L1 when L1 is a linker atom or group. Each L4 atom or group may interrupt the aliphatic chain, or may be positioned at its terminal carbon atom to connect the chain to an adjoining atom or group.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3)CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2)5CH2xe2x80x94, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2CHCHxe2x80x94, CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94, or xe2x80x94(CH2)2CCxe2x80x94 chains. Where appropriate each of said chains may be optionally interrupted by one or two atoms and/or groups L4 to form an optionally substituted heteroaliphatic chain. Particular examples include optionally substituted xe2x80x94L4CH2xe2x80x94, xe2x80x94CH2L4CH2xe2x80x94, xe2x80x94L4(CH2)2xe2x80x94, xe2x80x94CH2L4(CH2)2xe2x80x94, xe2x80x94(CH2)2L4CH2xe2x80x94, xe2x80x94L4(CH2)3xe2x80x94 and xe2x80x94(CH2)2L4(CH2)2xe2x80x94 chains. The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6 alkoxy, e.g. methoxy or ethoxy, thiol, C1-6 alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR12 and xe2x80x94N(R12)2 groups where R12 is an optionally substituted straight or branched alkyl group as defined below for R11. Where two R12 groups are present these may be the same or different. Particular examples of substituted chains represented by Alk1 include those specific chains just described substituted by one, two, or three halogen atoms such as fluorine atoms, for example chains of the type xe2x80x94CH(CF3)xe2x80x94, xe2x80x94C(CF3)2xe2x80x94, xe2x80x94CH2CH(CF3)xe2x80x94, xe2x80x94CH2C(CF3)2xe2x80x94, xe2x80x94CH(CF3)xe2x80x94 and xe2x80x94C(CF3)2CH2xe2x80x94.
Halogen atoms represented by R7 in compounds of the invention include fluorine, chlorine, bromine, or iodine atoms.
Examples of the substituents represented by R4 and R5 in compounds of formula (I) include atoms or groups xe2x80x94L2Alk3L3R7, xe2x80x94L2Alk3R7, xe2x80x94L2R7, xe2x80x94Alk3R7 and xe2x80x94R7 wherein L2, Alk3, L3 and R7 are as defined above. Particular examples of such substituents include xe2x80x94L2CH2L3R7, xe2x80x94L2CH(CH3)L3R7, xe2x80x94L2CH(CH2)2L3R7, xe2x80x94L2CH2R7, xe2x80x94L2CH(CH3)R7, xe2x80x94L2(CH2)2R7, xe2x80x94CH2R7, xe2x80x94CH(CH3)R7 and xe2x80x94(CH2)2R7 groups.
Thus each of R4 and R5 in compounds of the invention may be for example a hydrogen atom, a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, or a C1-6 alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, C1-6 alkylamino, e.g. methylamino or ethylamino, C1-6 hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxy C1-6 alkyl, e.g. carboxyethyl, C1-6 alkylthio e.g. methylthio or ethylthio, carboxy C1-6 alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6 alkoxy, e.g. methoxy or ethoxy, C6-12 aryl C1-6 alkyloxy e.g. benzyloxy, hydroxy C1-6 alkoxy, e.g. 2-hydroxyethoxy, halo C1-6 alkyl, e.g., trifluoromethyl, halo C1-6 alkoxy, e.g. trifluoromethoxy, C1-6 alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), amino C1-6 alkyl, e.g. aminomethyl or aminoethyl, C1-6 dialkylamino, e.g. dimethylamino or diethylamino, C1-6 alkylamino C1-6 alkyl, e.g. ethylaminoethyl, C1-6 dialkylamino C1-6 alkyl, e.g. diethylaminoethyl, amino C1-6 alkoxy, e.g., aminoethoxy, C1-6 alkylamino C1-6 alkoxy, e.g. methylaminoethoxy, C1-6 dialkylamino C1-6 alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk5 [where Alk5 is as defined below], C1-6 alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thio C1-6 alkyl, e.g., thiomethyl or thioethyl, thio C1-6 alkyl C6-12 aryl, e.g. thiobenzyl, sulphonyl (xe2x80x94SO3H), C1-6 alkylsulphinyl, e.g., methylsulphinyl, C1-6 alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2 NH2), C1-6 alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6 dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6 alkylaminocarbonyl, e.g. methylaminocarbonyl or ethyl aminocarbonyl, C1-6 dialkylaminocarbonyl, e.g., dimethylaminocarbonyl or diethylaminocarbonyl, amino C1-6 alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6 dialkylamino C1-6 alkylaminocarbonyl, e.g., diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6 alkylaminocarbonylamino, e.g., methyl-aminocarbonylamino or ethylaminocarbonylamino, C1-6 dialkylaminocarbonyl-amino, e.g., dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6 alkylaminocabonylC1-6 alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6 alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6 dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6 alkylaminothiocarbonyl C1-6 alkylamino, e.g. ethylaminothiocarbonylmethylamino, C1-6 alkylsulphonylamino, e.g. methylsulphonylamino or ethyl sulphonylamino, C1-6 dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6 alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6 dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C1-6 alkanoylamino, e.g. acetylamino, aminoC1-6 alkanoylamino e.g. aminoacetylamino, C1-6 dialkylamino-C1-6 alkanoylamino, e.g. dimethylaminoacetylamino, C1-6 alkanoylamino C1-6 alkyl, e.g. acetyl aminomethyl, C1-6 alkanoylamino C1-6 alkylamino, e.g. acetamidoethylamino, C1-6 alkoxycarbonylamino, e.g., methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino group.
Aromatic groups represented by the group Ar in compounds of the invention include, for example, monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups. Aromatic groups represented by the group Ar may be optionally substituted by one, two, three or more R13 atoms or groups as defined below.
Heteroaromatic groups represented by the group Ar in the compounds of the invention include for example C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example eight- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, Nxe2x80x94C1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl; 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, qunoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by Ar include one, two, three or more substituents, each selected from an atom or group R13 in which R13 is R13a or xe2x80x94Alk4(R13a)m, where R13a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR14 [where R14 is an xe2x80x94Alk3(R13a)m, aryl or heteroaryl group], xe2x80x94CSR14, xe2x80x94SO3H, xe2x80x94SO2R14 xe2x80x94SO2NH2, xe2x80x94SO2NHR14, xe2x80x94SO2N(R14)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR14, xe2x80x94CSNHR14, xe2x80x94CON[R14]2, xe2x80x94CSN(R14)2, xe2x80x94N(R12)SO2R14, xe2x80x94N(SO2R14)2, xe2x80x94NH(R11)SO2NH2, xe2x80x94N(R11)SO2NHR14, xe2x80x94N(R11)SO2N(R14)2, xe2x80x94N(R11)COR14, N(R11)CON(R14)2, xe2x80x94N(R11)CSN(R14)2, xe2x80x94N(R11)CSR14, xe2x80x94N(R11)C(O)OR14, xe2x80x94SO2NHet1 [where xe2x80x94NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)groups], xe2x80x94CONHet1, xe2x80x94CSNHet1, xe2x80x94N(R11)SO2NHet1, xe2x80x94N(R11)CONHet1, xe2x80x94N(R11)CSNHet1, xe2x80x94Het2, [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups] xe2x80x94SO2N(R11)Het2, xe2x80x94CON(R11)Het2, xe2x80x94CSN(R11)Het2, xe2x80x94N(R11)CON(R11)Het2, xe2x80x94N(R11)CSN(R11)Het2, aryl or heteroaryl group; Alk4 is a straight or branched C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R15)xe2x80x94 groups [where R15 is a hydrogen atom or C1-6 alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R11 or R14 groups are present in one of the above substituents, the R11 or R14 groups may be the same or different.
When in the group xe2x80x94Alk4(R13a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R13a may be present on any suitable carbon atom in xe2x80x94Alk4. Where more than one R13a substituent is present these may be the same or different and may be present on the same or different atom in xe2x80x94Alk4. Clearly, when m is zero and no substituent R13a is present the alkylene, alkenylene or alkynylene chain represented by Alk4 becomes an alkyl, alkenyl or alkynyl group.
When R13a is a substituted amino group it may be for example a group xe2x80x94NHR14 [where R14 is as defined above] or a group xe2x80x94N(R14)2 wherein each R14 group is the same or different.
When R13a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R13a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR14 or a xe2x80x94SR14 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R13a include groups of formula xe2x80x94CO2Alk5 wherein Alk5 is a straight or branched, optionally substituted C1-8 alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12 aryl C1-8 alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12 aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12 aryloxy C1-8 alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8 alkanoyloxy C1-8 alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12 aroyloxy C1-8 alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alks group include R13a substituents described above.
When Alk4 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, sbutylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R12)xe2x80x94 groups.
Aryl or heteroaryl groups represented by the groups R13a or R14 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the group Ar. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero, e.g. nitrogen atom, as appropriate.
When xe2x80x94NHet1 or xe2x80x94Het2 forms part of a substituent R13 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on xe2x80x94NHe1 or xe2x80x94Het2 include those R7 substituents described above.
Particularly useful atoms or groups represented by R13 include fluorine, chlorine, bromine or iodine atoms, or C1-6 alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, or thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, C1-6 alkylamino, e.g. methylamino or ethylamino, C1-6 hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6 alkyl, e.g. carboxyethyl, C1-6 alkylthio e.g. methylthio or ethylthio, carboxy C1-6 alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6 alkoxy, e.g. methoxy or ethoxy, hydroxy C1-6 alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C5-7 cycloalkoxy, e.g. cyclopentyloxy, halo C1-6 alkyl, e.g. trifluoromethyl, halo C1-6 alkoxy, e.g. trifluoromethoxy, C1-6 alkylamino, e.g. methylamino or ethylamino or propylamino, optionally substituted C6-12 aryl C1-6 alkylamino, e.g. benzylamino, fluorobenzylamino or hydroxyphenylethylamino, amino (xe2x80x94NH2), amino C1-6 alkyl, e.g. aminomethyl or aminoethyl, C1-6 dialkylamino, e.g. dimethylamino or diethylamino, amino C1-6 alklamino e.g. aminomethylamino, aminoethylamino or aminopropylamino, Het1 NC1-6 alkylamino e.g., morpholinopropylamino, C1-6 alkylamino C1-6 alkyl, e.g. ethylaminoethyl, C1-6 dialkylamino C1-6 alkyl, e.g. diethylaminoethyl, amino C1-6 alkoxy, e.g. aminoethoxy, C1-6 alkylamino C1-6 alkoxy, e.g. methylaminoethoxy, C1-6 dialkylamino C1-6 alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxy C1-6 alkylamino, e.g. hydroxyethylamino, hydroxypropylamino or hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk5 [where Alk5 is as defined above], C1-6 alkanoyl e.g. acetyl, propyryl or butyryl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g., thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphinyl, e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, C1-6 alkylsulphonyl, e.g. methylsulphonyl, ethylsulphonyl, propylsulphonyl, hexylsulphonyl or isobutylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6 alkylaminosulphonyl, e.g. methylaminosulphonyl, ethylaminosulphonyl or propylaminocsulphonyl, C1-6 dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, optionally substituted phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6 alkylaminocarbonyl, e.g. methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl, diethylaminocarbonyl or dipropylaminocarbonyl, amino C1-6 alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6 dialkylamino C1-6 alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6 alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6 dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6 alkylaminocabonyl C1-6 alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6 alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6 dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6 alkylaminothiocarbonyl C1-6 alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6 alkylsufphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6 dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6 alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6 dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonyl C1-6 alkyl-amino, optionally substituted phenylaminosulphonylamino, C1-6 alkanoylamino, e.g. acetylamino, amino C1-6 alkanoylamino e.g. aminoacetylamino, C1-6 dialkylamino C1-6 alkanoylamino, e.g., dimethylaminoacetylamino, C1-6 alkanoylamino C1-6 alkyl, e.g. acetylaminomethyl, C1-6 alkanoylamino C1-6 alkylamino, e.g. acetamidoethylamino, C1-6 alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylamino C1-6 alkyl e.g. benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R13 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6 alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R13 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the 5 aromatic or heteroaromatic group represented by Ar.
The presence of certain substituents in the compounds of formulae (1) and (2) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
R in the compounds of formulae (1) and (2) is preferably a xe2x80x94CO2H group.
In compounds of formulae (1) and (2), m is preferably 1 and Alk2 is preferably xe2x80x94CH2xe2x80x94.
R4 and R5 in the compounds of formulae (1) and (2) may be the same or different and is each preferably a hydrogen or halogen atom or an alkyl, alkoxy, hydroxy, nitro, cyano or xe2x80x94NR8R9 group.
R6 and Ra in the compounds of formulae (1) and (2) is each preferably a hydrogen atom.
Particularly useful classes of compounds according to the invention are those wherein Ar is an optionally substituted monocyclic aromatic or heteroaromatic group. One especially useful aromatic group when represented by Ar is phenyl. Especially useful heteroaromatic groups represented by Ar include optionally substituted monocyclic nitrogen containing heteroaromatic groups, particularly optionally substituted pyridyl, pyrimidinyl, pyridazinyl and triazinyl groups. Where the group is a triazinyl group it is preferably a 1,3,5 triazine.
Optional substituents which may be present on preferred Ar aromatic or heteroaromatic groups include for example one or two substituents selected from those R13 substituents described above.
Particularly useful R13 substituents of these types include a halogen atom, especially fluorine or chlorine, morpholinyl, thiomorpholinyl, optionally substituted piperidinyl, especially piperidinyl or 4-carboxypiperidinyl, pyrrolidinyl, optionally substituted piperazinyl, especially t-butyloxycarbonylpiperazinyl, thio C1-6 alkyl, especially thiomethyl, thioethyl or thiopropyl, optionally substituted thiobenzyl, especially thiobenzyl, halo C1-6 alkyl, especially trifluoromethyl, C1-6 alkyloxy, especially methoxy, ethoxy or propoxy, optionally substituted benzyloxy, especially benzyloxy, halo C1-6 alkoxy, especially trifluoromethoxy and difluoromethoxy, C1-6 alkylamino, especially methylamino, ethylamino or propylamino, C1-6 dialkylamino, especially dimethylamino or diethylamino, optionally substituted C6-12 aryl C1-6 alkylamino, especially benzylamino, 4-substituted benzyl, especially 4-fluorobenzylamino or 4-hydroxyphenylethylamino, aminoalkylamino, especially 3-aminopropylamino, Het1 N(C1-6 alkylamino), especially 3-morpholinopropylamino, optionally substituted phenoxy, especially phenoxy, hydroxy C1-6 alkylamino, especially 2-hydroxyethylamino, 3-hydroxypropylamino and 3-hydroxybutylamino, nitro, carboxyl, xe2x80x94CO2Alk5 [where Alk5 is as defined above], especially carboxymethyl and carboxyethyl, carboxamido, C1-6 alkylaminocarbonyl, especially methylaminocarbonyl, ethylaminocarbonyl and propylaminocarbonyl, C1-6 dialkylaminocarbonyl, especially dimethylaminocarbonyl, diethylaminocarbonyl or dipropylaminocarbonyl, C1-6 alkanoyl, especially acetyl, propyryl or butyryl, optionally substituted benzoyl, especially benzoyl, C1-6 alkylsulphinyl, especially methylsulphinyl, ethylsulphinyl or propylsulphinyl, Cl-alkylsulphonyl, especially methylsulphonyl, ethylsulphonyl, propylsulphonyl, hexylsulphonyl or isobutylsulphonyl, C1-6 alkylaminosulphonyl, especially ethylaminosulfonyl or propylamino-sulphonyl, C1-6 dialkylaminosulphonyl, especially diethylaminosulphonyl, C1-6 alkylaminocarbonyl, especially methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl, C1-6 dialkylaminocarbonyl, especially dimethylaminocarbonyl or diethylaminocarbonyl.
Particularly useful Alk4 groups when present in compounds of the invention include xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94 and xe2x80x94(CH2)3CH2xe2x80x94 groups.
Particularly useful compounds of the invention include:
S-3-[4-(N,N-dimethylaminocarbonyloxy)phenyl]-2-(6 propylsulphinylpyrimidin-4-ylamino)propanoic acid;
S-3-[4-(N,N-dimethylaminocarbonyloxy)phenyl]-2-(6 diethylaminosulphonylpyrimidin-4-ylamino)propanoic acid; and
S-3-[4-(N-morpholinocarbonyloxy)phenyl]-2-(6 -diethylaminosulphonylpyrimidin-4-ylamino)propanoic acid;
and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are potent and selective inhibitors of xcex14 integrins. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
The compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formulae (1) and (2) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formulae (1) and (2) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
As used herein, the following terms have the following meanings unless more limited definitions are used:
As used herein, xe2x80x9calkylxe2x80x9d refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxylcycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-Oxe2x80x94xe2x80x9d which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cAlkenoxyxe2x80x9d refers to the group xe2x80x9calkenyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cSubstituted alkenoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkenyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cAcylxe2x80x9d refers to the groups Hxe2x80x94C(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, alkynylxe2x80x94C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94 cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, substituted aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94, substituted heteroaryl-C(O), heterocyclic-C(O)xe2x80x94, and substituted heterocyclic-C(O)xe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cThiocarbonylaminoxe2x80x9d refers to the group xe2x80x94C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, alkenyl-C(O)Oxe2x80x94, substituted alkenyl-C(O)Oxe2x80x94, alkynyl-C(O)Oxe2x80x94, substituted alkynyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, substituted aryl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, substituted heteroaryl-C(O)Oxe2x80x94, heterocyclic-C(O)Oxe2x80x94, and substituted heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxysulfonylxe2x80x9d refers to the groups alkyl-SO2Oxe2x80x94, substituted alkyl-SO2Oxe2x80x94, alkenyl-SO2Oxe2x80x94, substituted alkenyl-SO2Oxe2x80x94, alkynyl-SO2Oxe2x80x94, substituted alkynyl-SO2Oxe2x80x94, aryl-SO2Oxe2x80x94, substituted aryl-SO2Oxe2x80x94, cycloalkyl-SO2Oxe2x80x94, substituted cycloalkyl-SO2Oxe2x80x94, heteroaryl-SO2Oxe2x80x94, substituted heteroaryl-SO2Oxe2x80x94, heterocyclic-SO2Oxe2x80x94, and substituted heterocyclic-SO2Oxe2x80x94 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-hetero-cyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAmidinoxe2x80x9d refers to the group H2NC(xe2x95x90NH)xe2x80x94 and the term xe2x80x9calkylamidinoxe2x80x9d refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(xe2x95x90NH)xe2x80x94).
xe2x80x9cThioamidinoxe2x80x9d refers to the group RSC(xe2x95x90NH)xe2x80x94 where R is hydrogen or alkyl.
xe2x80x9cAminoxe2x80x9d refers to the group xe2x80x94NH2.
xe2x80x9cSubstituted aminoxe2x80x9d refers to the group xe2x80x94NRR, where each R group is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic, provided that both R groups are not hydrogen; or the R groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
xe2x80x9cAminoacylxe2x80x9d refers to the groups xe2x80x94NRC(O)alkyl, xe2x80x94NRC(O)substituted alkyl, xe2x80x94NRC(O)cycloalkyl, xe2x80x94NRC(O)substituted cycloalkyl, xe2x80x94NRC(O)alkenyl, xe2x80x94NRC(O)substituted alkenyl, xe2x80x94NRC(O)alkynyl, xe2x80x94NRC(O)substituted alkynyl, xe2x80x94NRC(O)aryl, xe2x80x94NRC(O)substituted aryl, xe2x80x94NRC(O)heteroaryl, xe2x80x94NRC(O)substituted heteroaryl, xe2x80x94NRC(O)heterocyclic, and xe2x80x94NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminosulfonylxe2x80x9d refers to the groups xe2x80x94NRSO2alkyl, xe2x80x94NRSO2substituted alkyl, xe2x80x94NRSO2cycloalkyl, xe2x80x94NRSO2substituted cycloalkyl, xe2x80x94NRSO2alkenyl, xe2x80x94NRSO2substituted alkenyl, xe2x80x94NRSO2alkynyl, xe2x80x94NRSO2substituted alkynyl, xe2x80x94NRSO2aryl, xe2x80x94NRSO2substituted aryl, xe2x80x94NRSO2heteroaryl, xe2x80x94NRSO2substituted heteroaryl, xe2x80x94NRSO2heterocyclic, and xe2x80x94NRSO2substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonyloxyxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-alkenyl, xe2x80x94NRC(O)O-substituted alkenyl, xe2x80x94NRC(O)O-alkynyl, xe2x80x94NRC(O)O-substituted alkynyl, xe2x80x94NRC(O)O-cycloalkyl, xe2x80x94NRC(O)O-substituted cycloalkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-substituted aryl, xe2x80x94NRC(O)O-heteroaryl, xe2x80x94NRC(O)O-substituted heteroaryl, xe2x80x94NRC(O)O-heterocyclic, and xe2x80x94NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminosulfonyloxyxe2x80x9d refers to the groups xe2x80x94NRSO2O-alkyl, xe2x80x94NRSO2O-substituted alkyl, xe2x80x94NRSO2O-alkenyl, xe2x80x94NRSO2O-substituted alkenyl, xe2x80x94NRSO2O-alkynyl, xe2x80x94NRSO2O-substituted alkynyl, xe2x80x94NRSO2O-cycloalkyl, xe2x80x94NRSO2O-substituted cycloalkyl, xe2x80x94NRSO2O-aryl, xe2x80x94NRSO2O-substituted aryl, xe2x80x94NRSO2O-heteroaryl, xe2x80x94NRSO2O-substituted heteroaryl, xe2x80x94NRSO2O-heterocyclic, and xe2x80x94NRSO2O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxycarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NH2, xe2x80x94OC(O)NRR, xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NR-substituted alkyl, xe2x80x94OC(O)NR-alkenyl, xe2x80x94OC(O)NR-substituted alkenyl, xe2x80x94OC(O)NR-alkynyl, xe2x80x94OC(O)NR-substituted alkynyl, xe2x80x94OC(O)NR-cycloalkyl, xe2x80x94OC(O)NR-substituted cycloalkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-substituted aryl, xe2x80x94OC(O)NR-heteroaryl, xe2x80x94OC(O)NR-substituted heteroaryl, xe2x80x94OC(O)NR-heterocyclic, and xe2x80x94OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxythiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(S)NH2, xe2x80x94OC(S)NRR, xe2x80x94OC(S)NR-alkyl, xe2x80x94OC(S)NR-substituted alkyl, xe2x80x94OC(S)NR-alkenyl, xe2x80x94OC(S)NR-substituted alkenyl, xe2x80x94OC(S)NR-alkynyl, xe2x80x94OC(S)NR-substituted alkynyl, xe2x80x94OC(S)NR-cycloalkyl, xe2x80x94OC(S)NR-substituted cycloalkyl, xe2x80x94OC(S)NR-aryl, xe2x80x94OC(S)NR-substituted aryl, xe2x80x94OC(S)NR-heteroaryl, xe2x80x94OC(S)NR-substituted heteroaryl, xe2x80x94OC(S)NR-heterocyclic, and xe2x80x94OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxysulfonylaminoxe2x80x9d refers to the groups xe2x80x94OSO2NH2, xe2x80x94OSO2NRR, xe2x80x94OSO2NR-alkyl, xe2x80x94OSO2NR-substituted alkyl, xe2x80x94OSO2NR-alkenyl, xe2x80x94OSO2NR-substituted alkenyl, xe2x80x94OSO2NR-alkynyl, xe2x80x94OSO2NR-substituted alkynyl, xe2x80x94OSO2NR-cycloalkyl, xe2x80x94OSO2NR-substituted cycloalkyl, xe2x80x94OSO2NR-aryl, xe2x80x94OSO2NR-substituted aryl, xe2x80x94OSO2NR-heteroaryl, xe2x80x94OSO2NR-substituted heteroaryl, xe2x80x94OSO2NR-heterocyclic, and xe2x80x94OSO2NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(O)NRR, xe2x80x94NRC(O)NR-alkyl, xe2x80x94NRC(O)NR-substituted alkyl, xe2x80x94NRC(O)NR-alkenyl, xe2x80x94NRC(O)NR-substituted alkenyl, xe2x80x94NRC(O)NR-alkynyl, xe2x80x94NRC(O)NR-substituted alkynyl, xe2x80x94NRC(O)NR-aryl, xe2x80x94NRC(O)NR-substituted aryl, xe2x80x94NRC(O)NR-cycloalkyl, xe2x80x94NRC(O)NR-substituted cycloalkyl, xe2x80x94NRC(O)NR-heteroaryl, and xe2x80x94NRC(O)NR-substituted heteroaryl, xe2x80x94NRC(O)NR-heterocyclic, and xe2x80x94NRC(O)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminothiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(S)NRR, xe2x80x94NRC(S)NR-alkyl, xe2x80x94NRC(S)NR-substituted alkyl, xe2x80x94NRC(S)NR-alkenyl, xe2x80x94NRC(S)NR-substituted alkenyl, xe2x80x94NRC(S)NR-alkynyl, xe2x80x94NRC(S)NR-substituted alkynyl, xe2x80x94NRC(S)NR-aryl, xe2x80x94NRC(S)NR-substituted aryl, xe2x80x94NRC(S)NR-cycloalkyl, xe2x80x94NRC(S)NR-substituted cycloalkyl, xe2x80x94NRC(S)NR-heteroaryl, and xe2x80x94NRC(S)NR-substituted heteroaryl, xe2x80x94NRC(S)NR-heterocyclic, and xe2x80x94NRC(S)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminosulfonylaminoxe2x80x9d refers to the groups xe2x80x94NRSO2NRR, xe2x80x94NRSO2NR-alkyl, xe2x80x94NRSO2NR-substituted alkyl, xe2x80x94NRSO2NR-alkenyl, xe2x80x94NRSO2NR-substituted alkenyl, xe2x80x94NRSO2NR-alkynyl, xe2x80x94NRSO2NR-substituted alkynyl, xe2x80x94NRSO2NR-aryl, xe2x80x94NRSO2NR-substituted aryl, xe2x80x94NRSO2NR-cycloalkyl, xe2x80x94NRSO2NR-substituted cycloalkyl, xe2x80x94NRSO2NR-heteroaryl, and xe2x80x94NRSO2NR-substituted heteroaryl, xe2x80x94NRSO2NR-heterocyclic, and xe2x80x94NRSO2NR-substituted heterocyclic, where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d or xe2x80x9cArxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls include phenyl and naphthyl.
Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 which includes, by way of example, phenoxy, naphthoxy, and the like.
xe2x80x9cSubstituted aryloxyxe2x80x9d refers to substituted aryl-Oxe2x80x94 groups.
xe2x80x9cAryloxyarylxe2x80x9d refers to the group xe2x80x94aryl-Oxe2x80x94aryl.
xe2x80x9cSubstituted aryloxyarylxe2x80x9d refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
xe2x80x9cSubstituted cycloalkylxe2x80x9d and xe2x80x9csubstituted cycloalkenylxe2x80x9d refer to a cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkoxyxe2x80x9d refers to xe2x80x94O-cycloalkyl groups.
xe2x80x9cSubstituted cycloalkoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkyl groups.
xe2x80x9cCycloalkenoxyxe2x80x9d refers to xe2x80x94O-cycloalkenyl groups.
xe2x80x9cSubstituted cycloalkenoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkenyl groups.
xe2x80x9cGuanidinoxe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRR, xe2x80x94NRC(xe2x95x90NR)NR-alkyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NR-alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-aryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NR-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NR-heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NR-substituted heterocyclic where each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cGuanidinosulfonexe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRSO2-alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heteroaryl, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heterocyclic where each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Additionally, the heteroatoms of the heteroaryl group may be oxidized, i.e., to form pyridine N-oxides or 1,1-dioxo-1,2,5-thiadiazoles and the like. Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1-oxo-1,2,5-thiadiazolyl and 1,1-dioxo-1,2,5-thiadiazolyl. The term xe2x80x9cheteroaryl having two nitrogen atoms in the heteroaryl ringxe2x80x9d refers to a heteroaryl group having two, and only two, nitrogen atoms in the heteroaryl ring and optionally containing 1 or 2 other heteroatoms in the heteroaryl ring, such as oxygen or sulfur
xe2x80x9cSubstituted heteroarylxe2x80x9d refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cHeteroaryloxyxe2x80x9d refers to the group xe2x80x94O-heteroaryl and xe2x80x9csubstituted heteroaryloxyxe2x80x9d refers to the group xe2x80x94O-substituted heteroaryl.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl.
xe2x80x9cSubstituted heterocyclicxe2x80x9d refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cHeterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-heterocyclic and xe2x80x9csubstituted heterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-substituted heterocyclic.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkylxe2x80x9d refers to the groups xe2x80x94S-alkyl
xe2x80x9cSubstituted thioalkylxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThiocycloalkylxe2x80x9d refers to the groups xe2x80x94S-cycloalkyl.
xe2x80x9cSubstituted thiocycloalkylxe2x80x9d refers to the group xe2x80x94S-substituted cycloalkyl.
xe2x80x9cThioarylxe2x80x9d refers to the group xe2x80x94S-aryl and xe2x80x9csubstituted thioarylxe2x80x9d refers to the group xe2x80x94S-substituted aryl.
xe2x80x9cThioheteroarylxe2x80x9d refers to the group xe2x80x94S-heteroaryl and xe2x80x9csubstituted thioheteroarylxe2x80x9d refers to the group xe2x80x94S-substituted heteroaryl.
xe2x80x9cThioheterocyclicxe2x80x9d refers to the group xe2x80x94S-heterocyclic and xe2x80x9csubstituted thioheterocyclicxe2x80x9d refers to the group xe2x80x94S-substituted heterocyclic.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R-R6 (including Ra), Ar, Alk2, m and r, when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) and formula (2) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. For convenience the processes described below all refer to a preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formula (2).
Thus according to a further aspect of the invention, a compound of formula (1) in which R is a xe2x80x94CO2H group may be obtained by hydrolysis of an ester of formula (3): 
where Rb is an alkyl group, for example a C1-6alkyl group as described above.
The hydrolysis may be performed using either an acid or a base depending on the nature of Rb, for example an organic acid such as trifluoroacetic acid or an inorganic base such as lithium or potassium hydroxide optionally in an aqueous organic solvent such as an amide, e.g., a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g. methanol at around ambient temperature. Where desired, mixtures of such solvents may be used.
Esters of formula (3) may be prepared by coupling an amine of formula (4): 
or a salt thereof with a reagent Arxe2x80x94X1 where X1 is a leaving group. Particular leaving groups represented by X1 include for example halogen atoms such as fluorine, chlorine or bromine atoms or sulphonyloxy groups such as a methylsulphonyloxy group.
The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an alcohol, e.g. methanol or ethanol, at a temperature from around ambient to the reflux temperature, optionally in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or N,N-diisopropylethylamine, or a cyclic amine, such as N-methylmorpholine or pyridine.
Where desired, compounds of formula (4) may be linked to a suitable solid support, for example via their carboxylate group (Rb is H), and subsequently converted to compounds of formula (1) linked to the solid support via the methods just described. Displacement from the resin by any convenient method for example by cleavage using an acid such as trifluoroacetic acid, then gives the desired compound of formula (1). Particular examples of such solid-phase syntheses are given in the Examples herein.
The amines of formula (4) may be obtained from simpler, known compounds by one or more standard synthetic methods employing Cxe2x80x94C bond formation substitution, 1,4-addition, oxidation, reduction or cleavage reactions. Particular Cxe2x80x94C bond forming reactions include the HornerEmmons and Wittig reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formulae (1) and (2) where appropriate functional groups exist in these compounds. Additionally, although a number of the intermediates ArX1 for use in the coupling reaction described above are known, others can be derived therefrom using these standard synthetic methods.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds of formula II can be prepared from the phenolic intermediate by reaction with, for example, 4-nitrophenyl chloroformate followed by reaction with an amine of the formula
R1R2NH
where R1 and R2 are as defined above. Further examples of this reaction are set forth in U.S. patent application Ser. No. 09/489,377 and WO 00/18759 both of which are incorporated herein by reference in its entirety.
Salts of compounds of formula (1) and (2) may be prepared by reaction of a compound of formula (1) or (2) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chromatography, recrystalliation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention. Examples 1-168 illustrate reaction schemes for use in preparing prior art compounds and Example 169 shows how such reaction schemes could be used to prepare compounds of this invention. All temperatures are in xc2x0 C. The following abbreviations are used:
A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [generated from nBuLi (2.5M solution hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.108, 5.7 ml, 40.6 mmol)] in THF (25 ml) at xe2x88x9278xc2x0 then CO2 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2 h, then quenched with water (20 ml) and partitioned between diethylether (100 ml) and 1 M NaOH (100 ml). The aqueous layer was separated and acidified to pH1 with concentrated hydrochloric acid and then extracted with 10% MeOH in DCM (100 mlxc3x973). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid that was recrystallised from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.638, 41%): xcex4H (DMSO d6) 8.72 (2H, s).
A slurry of Intermediate 1 (51.2 g, 0.267 mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops) and heated to reflux for 4 h. The reaction was concentrated in vacuo and azeotroped with toluene (2xc3x9750 ml) to give the acid chloride derivative of intermediate 1 as a yellow solid which was used without further purification. A solution of (S)-ethyl-3-(4-aminophenyl)-2-(t-butoxycarbonylamino)propionate (130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0xc2x0 and treated with NMM (56.0 ml, 0.51 mol), stirred 5 minutes and then a solution of the acid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise keeping the reaction temperature below 5xc2x0. The reaction was stirred for 1 h, quenched with NaHC3 solution (500 ml), the organic layer separated, washed with NaHCO3 solution (500 ml), 10% citric acid solution (500 ml) and NaHCO3 solution (500 ml), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was recrystallised (EtOAc/Hexane) to give the title compound (140 g, 69%): xcex4H (DMSO d6) 8.80 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.00 (3H, m), 3.40 (2H, br. s), 2.90 (1H, m), 2.80 (1H, m), 1.30 (9H, s), 1.25 (3H, t); m/z (EI+, 70V) 504.
A solution of Intermediate 2 (70.0 g, 0.146 mol) in EtOAc (500 ml) and 1,4dioxan (50 ml) was treated with a solution of HCl in EtOAc (500 ml, 3M), and stirred at room temperature for 4 h. The reaction was concentrated in vacuo to give a yellow solid which was triturated with Et2O then recrystallised (EtOAc/hexane) to give the title compound (59.3 g, 92%): xcex4H (DMSO d6) 11.10 (1H, s), 8.70 (2H, s), 7.55 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H, m), 1.10 (3H, m); m/z (EI+, 70V) 382.
The title compound was prepared in a similar manner to Intermediate 3 starting from (S)-methyl-3-(4-aminophenyl)-2-(t-butoxycarbonylamino)propionate and Intermediate 1: xcex4H (DMSO d6) 11.08 (1H, s), 8.77 (2H, s), 8.73 (3H, br. m), 7.63 (2H, d, J 8.5 Hz), 7.25 (2H, d, J 8.5 Hz), 4.24 (1H, m), 3.70 (3H, s), 3.16 (2H, m); m/z (EI+, 70V) 368 and 370.
A solution of 3,5-dichloropyridine-4-carboxaldehyde (1.34 g, 7.6 mmol) in MeOH (10 ml) was treated with NaBH4 (0.29 g, 7.6 mmol) and stirred at room temperature for 2 h. The reaction was quenched with water (5 ml) and concentrated in vacuo. The residue was partitioned between EtOAc (20 ml) and 10% HCl (10 ml). The aqueous layer was extracted with EtOAc and the combined organic extracts washed with 10% NaHCO3 solution, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (1.05 g, 78%): xcex4H (CDCl3) 8.52 (2H, s), 4.94 (2H, br. s), 2.28 (1H, br. s).
A solution of Intermediate 5 (0.50 g, 2.80 mmol) in DCM (10 ml) was treated with thionyl bromide (3.51 g, 1.32 ml, 16.9 mmol) and heated to reflux for 3 h. The reaction was quenched with 10% NaHCO3 solution (10 ml) and extracted with DCM (25 ml). The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil that solidified on standing (0.65 g, 96%) and was used without further purification: xcex4H (CDCl3) 8.50 (2H, s), 4.63 (2H, s); m/z (EI+, 60V) 242.
The title compound was obtained by reaction of N-Boc-L-tyrosine ethyl ester with Intermediate 6 in the presence of sodium hydride, followed by Boc deprotection, using methods well known to a person skilled in the art: xcex4H (DMSO d6) 8.79-8.60 (3H, m), 7.20 (2H, d, J 8.6 Hz), 7.00 (2H, d, J 8.6 MHz), 5.21 (2H, s), 4:34-4.20 (1H, m), 3.67 (3H, s); m/z (EI+, 70V) 355 and 357.
A solution of 4-nitro-L-phenylalanine ethyl ester (3.22 g, 13.53 mmol), DIPEA (2.35 ml, 1.75 g, 13.56 mmol) and 4,6-dichloropyrimidine (2.02 g, 13.55 mmol) in absolute ethanol (16 ml) was stirred at 70xc2x0 for 18 h under N2. The volatiles were removed in vacuo and the residue partitioned between EtOAc (70 ml) and water (40 ml). The phases were separated and the aqueous phase re-extracted with EtOAc (2xc3x9730 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark oil. Chromatography (silica, 2% MeOH/DCM) afforded the title compound as an orange oil which slowly solidified (4.03 g, 85%); xcex4H (CDCl3,) 8.39 (1H, s), 8.13 (2H, d, J 8.7 Hz), 7.28 (2H, d, J 8.7 Hz), 6.43 (1H, s), 5.55 (1H, br d, J 7.0 Hz), 5.10-5.00 (1H, br m), 4.21 (2H, q, J 7.1 Hz), 3.27 (1H, dd, J 13.8, 6.0 Hz), 3.27 (1H, dd, J 13.8, 5.7 Hz) and 1.26 (3H, t, J 7.1 Hz); m/z (EI+, 100V) 351.
A mixture of Intermediate 8 (1 g, 2.85 mmol) and 10% palladium on activated carbon (100 mg) in absolute ethanol (40 ml) was stirred under a hydrogen atmosphere (balloon) at room temperature for 1.5 h. After degassing and N2 flushing, the catalyst was removed by filtration through a Celite(copyright) pad and washed with DCM. The filtrate was evaporated in vacuo and the obtained yellow oil subjected to chromatorgaphy (silica: 3% MeOH/DCM). The title compound was isolated as a yellow oil (0.42 g, 46%) xcex4H (CDCl3) 8.33 (1H, s), 6.86 (2H, d, J 8.4 Hz), 6.56 (2H, d, J 8.4 Hz), 6.30 (1H, s), 5.27 (1H, br s), 4.84 (1H, br s), 4.19 (2H, q, J 7.1 Hz), 3.64 (2H, br s), 3.10 (1H, dd, J 14.0, 5.6 Hz), 3.01 (1H, dd, J 14.0, 6.1 Hz) and 1.26 (3H, t, J 7.1 Hz); m/z (EI+, 100V) 321.
Intermediate 3 (0.5 g, 1.19 mmol) in dry acetonitrile (5 ml) under nitrogen was added to 2,4 dichloro-6-methoxy-1,3,5-triazine (0.26 g, 1.43 mmol). The mixture was cooled to xe2x88x9230xc2x0 and DIPEA (0.46 ml) was added slowly over 10 min. The reaction was allowed to warm to 5xc2x0 over 2 h and then ethyl acetate and aqueous sodium bicarbonate were added and the mixture shaken and separated. The organic layer was washed with water, dried (MgSO4) and the solvent removed in vacuo. The product was purified by flash chromatography (silica; EtOAC/Hexane 1:1) to afford the title compound as a white solid (0.53 g, 85%): xcex4H (DMSO d6) 10.55 (1H, s), 8.70 (2H, s), 8.51-8.40 (1H, m), 7.50 (2H, d, J 8.4 Hz), 7.29 (2H, d, J 84 Hz), 4.60 (1H, m), 4.12 (2H, d, J 8.4 Hz), 3.87 (3H, s), 3.23-3.15 (2H, m), 1.16 (3H, t, J 7.2 Hz); m/z (EI+, 70V) 527.
A mixture of L-tyrosine ethyl ester hydrochloride (0.50 g, 2.0 mmol) and DIPEA (0.74 ml, 4.4 mmol) in CH3CN (8 ml) was stirred at room temperature for 15 minutes and then 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.43 g, 2.2 mmol) was added, and the reaction stirred overnight then concentrated in vacuo. The residue was partitioned between EtOAc (50 ml) and NaHCO3 solution (50 ml). The organic layer was washed with 10% citric acid solution (50 ml), NaHCO3 solution (50 ml) and water (50 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless gum (0.48 g, 68%): xcex4H (DMSO d6) 6.90 (2H, d), 6.65 (2H, d), 5.90 (1H, m), 4.90 (1H, m), 4.10 (2H, m), 3.95 (3H, s), 3.90 (3H, s), 3.10 (2H, m), 1.20 (3H, t, J 7.1 Hz); m/z (EI+ 70V) 349.
Propanethiol (1.99 ml, 22 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 880 mg, 22 mmol) in THF (50 ml). After 10 min, a solution of 2,3-dichloropyrazine (1.49 g, 10 mmol) in THF (15 ml) was added and the mixture stirred at room temperature overnight. The reaction was quenched with water and the solvent removed in vacuo. The residue was dissolved in EtOAc, washed with water, 10% NaOH solution and brine, dried (Na2SO4) and evaporated in vacuo to give a pale yellow oil (2.7 g). This was dissolved in DCM (100 ml) at 0xc2x0, and mCPBA (57-86%, xcx9c40 mmol, 12.1 g) was added in portions. The mixture was stirred at room temperature overnight, then treated with Na2SO3 (aq). The organic phase was washed with NaHCO3 (aq), dried (Na2SO4) and evaporated in vacuo to give the title compound as a white solid (3.18 g): xcex4H (CDCl3) 8.94 (2H, s), 3.58-3.63 (4H, m), 2.10-1.88 (4H, m), 1.10 (6H, t, J 7.4 Hz); m/z (EI+, 70V) 293.
The title compound was prepared by the method of Intermediate 12 from 4,6-dichloropyrimidine: xcex4H (DMSO d6) 9.77 (1H, d, J 1.3 Hz), 8.40 (1H, d, J 1.3 Hz), 3.61-3.56 (4H, m), 1.75-1.65 (4H, m), 0.97 (6H, t, J 7.5 Hz); m/z (EI+, 70V) 293.
A solution of phenol (564 mg, 6 mmol) in THF (5 ml) was added to a suspension of sodium hydride (60% in mineral oil, 240 mg, 6 mmol) in THF (10 ml). After 10 min 2,3-dichloroquinoxaline (995 mg, 5 mmol) was added. The mixture was stirred for 3 days. The solvent was removed in vacuo, the residue was dissolved in EtOAc, washed with NaOH (1M), dried (Na2SO4) and evaporated in vacuo to give a yellow solid. Recrystallisation from diisopropylether gave the title compound as off-white needles: xcex4H (DMSO d6) 8.01-7.98 (1H, m), 7.77-7.67 (3H, m), 7.53-7.48 (2H, m), 7.37-7.30 (3H, m); m/z (EI+, 70V) 257.
Ethyl 2-(diethoxyphosphoryl)acetate (5.0 ml, 25.2 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 1.10 g, 27.6 mmol) in THF (40 ml) at 0xc2x0. After 30 min at room temperature, a solution of 4-nitrobenzylbromide (5.42 g, 25.2 mmol) in THF (40 ml) was added over 30 min. The reaction mixture was stirred for 2 h at room temperature, quenched with water and partitioned between Et2O and water. The aqueous phase was extracted with Et2O and the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; MeOH/DCM, 1:49) gave the title compound as a pale yellow oil (2.01 g): xcex4H (CDCl3) 8.13 (2H, d, J 8.8 Hz), 7.37 (2H, d, J 8.8 Hz), 4.23-4.06 (6H, m), 3.37-3.20 (3H, m), 1.35 (6H, t, J 7.1 Hz), 1.16 (3H, t, J 7.1 Hz): m/z (EI+, 70V) 360.
A mixture of Intermediate 15 (4.5 g, 12.0 mmol) and tin(II) chloride dihydrate (15 g) in ethanol was stirred overnight. The solvent was removed in vacuo. DCM (100 ml) and 1M NaOH (100 ml) was added and the white precipitate removed by filtration. The organic phase of the filtrate was separated and evaporated in vacuo. The residue was acidified to pH1 with dil. HCl and extracted with diethyl ether. The aqueous phase was basified to pH10 with Na2CO3 and extracted with EtOAc. The EtOAc extracts were dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; MeOH/DCM 5:95) gave the title compound as a yellow oil (2.19 g): xcex4H CDCl3) 6.98 (2H, d, J 8.2 Hz), 6.59 (2H, d, J 8.5 Hz), 4.22-4.04 (6H, m), 3.25-3.02 (3H, m), 1.34 (6H, m), 1.16 (3H, t, J 7.1 Hz): m/z (EI+, 70V) 330.
A solution of 3,5-dichloropyrid-4-ylcarbonyl chloride (1.41 g, 6.7 mmol) in THF (10 ml) was added to a solution of Intermediate 16 (2.19 g, 6.7 mmol) and NMM (0.88 ml, 8.0 mmol) in THF (40 ml). The mixture was stirred at room temperature overnight then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic yers washed with 10% aqueous HCl and NaHCO3 (aq), dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; MeOH/DCM 95) gave the title compound as a yellow oil (2.61 g): xcex4H (CDCl3) 8.55 (2H, s), 8.08 (1H, br. s), 7.55 (2H, d, J 8.5 Hz), 7.21 (2H, d, J 8.5 Hz), 4.19-4.08 6H, m), 3.25-3.10 (3H, m), 1.35 (3H, t, J 7.1 Hz), 1.34 (3H, t, J 7.1 Hz), 1.18 (3H, t, J 7.1 Hz).
A mixture of Intermediate 17 (1.74 g, 3.66 mmol), potassium carbonate (1.48 g, 10.7 mmol) and aqueous paraformaldehyde (37% wt, 10 ml) was heated at reflux for 4 h. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; EtOAc/Hexane 50:50) gave the title compound as a white solid (1.09 g): xcex4H (CDCl3) 8.52 (1H, br. s), 8.44 (2H, br. s), 7.49 (2H, d, J 8.5 Hz), 7.18 (2H, d, J 8.5 Hz), 6.22 (1H, br. s), 5.49 1H, br. s), 4.15 (2H, q, J 7.2 Hz), 3.60 (2H, br. s), 1.27 (3H, t, J 7.2 Hz).
A mixture of Intermediate 18 (1.50 g, 3.7 mmol) and liquid ammonia (10 ml) was kept in a sealed vessel for 3 d at room temperature. Column chromatography (silica; MeOH/DCM 1:9 to 1:4) gave the title compound as a colourless oil (1.00 g): xcex4H (DMSO d6) 10.83 (1H, s), 8.78 (2H, d, J 8.5 Hz), 7.54 (2H, d, J 8.5 Hz), 7.16 (2H, d, J 8.5 Hz), 4.00 (2H, q, J 7.1 Hz), 3.29 (2H, br. s), 2.83-2.61 (5H, m), 1.10 (3H, t, J 7.1 Hz): m/z (EI+, 70V) 396.
A solution of the compound of Intermediate 3 (free amine) (2.80 g, 7.40 mmol), glacial acetic acid (1.4 ml, 24.50 mmol), isoamyl nitrite (1 ml, 7.40 mmol) in 100 ml anhydrous chloroform were stirred at reflux under nitrogen for 1 h. On cooling the solution was washed with water (2xc3x9725 ml), saturated NaHCO3 (2xc3x9725 ml), water (2xc3x9725 ml), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a yellow solid (2.1 g, 100%): xcex4H (CDCl3) 8.56 (2H, s), 7.72 (1H, br. s), 7.55 (2H, d, J 8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 4.22 (2H, q, J 7.1 Hz), 3.62 (2H, s), 1.25 (3H, t, J 7.1 Hz).
2-Amino-5-chloropyridine (10.0 g, 77 mmol), acetonyl acetone (8.8 g, 77 mmol) and a catalytic amount of p-toluenesulphonic acid in anhydrous toluene (250 ml) was heated to reflux for 5 h under Dean and Stark conditions. The solvent was removed in vacuo, the residue slurried in hexane (250 ml), filtered through celite and the solvent removed in vacuo to give the title compound as a yellow oil (16.0 g): xcex4H (CDCl3) 8.57 (1H, dd, J 2.7, 0.6 Hz), 7.78 (1H, dd, J 8.4, 2.7 Hz), 7.17 (1H, m, J 7.5, 0.5 Hz), 5.91 (2H, s), 2.14 (6H, s).
To a solution of LDA (12.3 mmol) in anhydrous toluene (6 ml) at xe2x88x9278xc2x0 under nitrogen was added Intermediate 21 (2.3 g, 11.2 mmol) in THF (6 ml) dropwise over 15 min. After stirring a further 15 min at this temperature n-propyl disulfide (1.92, 12.8 mmol) in THF (2 ml) was added dropwise maintaining the temperature at xe2x88x9278xc2x0. On completion of the addition the reaction was allowed to warm to room temperature and quenched with 10% NH4Cl solution, diluted with EtOAc (50 ml) and the phases separated. The organic phase was washed with water (2xc3x9710 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by chromatography (silica; 2% EtOAc/Hexane) to give the title compound (2.9 g) as a yellow solid: xcex4H (CDCl3) 8.39 (1H, s), 7.00 (1H, s), 5.92 (2H, s), 2.91 (2H, d, J 7.4 Hz), 2.15 (6H, s), 1.74 (2H, m), 1.09 (3H, t, J 7.4 Hz).
Intermediate 22 (1.3 g, 4.6 mmol) and hydroxylamine hydrochloride (1.6 g, 23 mmol) were heated to reflux in EtOH (12 ml) and water (3.5 ml) for 16 h. The cooled solution was poured onto conc HCl (12 ml)/water (48 ml) and the resulting solid filtered, washed with water and dried to give the title compound as a brown solid (550 mg): xcex4H (CDCl3) 8.11 (1H, s), 6.91 (1H, s), 3.01 (2H, t, J 7.3 Hz), 1.64 (2H, m), 1.00 (3H, t, J 7.3 Hz)): m/z (EI+, 70V) 203.
Paramax Wang resin (Advanced Chemtech, 8.0 g, 0.69 mmol/g, 5.52 mmol equivalent) in DCM (100 ml) was treated with N-xcex1-FMOC-4-nitro-L-phenylalanine (11.93 g, 27.66 mmol), diisopropylcarbodiimide (4.32 ml, 27.6 mmol) and 4-N,N-dimethylaminopyridine (0.67 g, 5.52 mmol) and mixture was agitated at room temperature for 16 h. The resin was filtered and washed with DMF, methanol and DCM, then air-dried. The resin was then treated with stannous chloride dihydrate (12.5 g, 55.2 mmol) in DMF (100 ml) at room temperature for 6 h, washed with DMF, methanol and DCM, then air dried overnight. The resin was treated with pyridine (4.44 ml, 55.2 mmol), 3,5-dichloropyrid-4-carbonyl chloride 3.52 g, 16.56 mmol) and 4-N,N-dimethylamino pyridine (0.67 g, 5.52 mmol) in DCM (100 ml). The reaction mixture was agitated at room temperature for 16 h. The resin was then washed with DMF, methanol and DCM, then with two 50 ml portions of a 10% solution of pyridine in DMF (100 ml). The resin was further washed with hot ethanol (2xc3x97100 ml), DMF, methanol and DCM then air-dried to give the title compound.
A portion of Intermediate 24 (3.0 g) was treated twice with a 20% solution of piperidine in DMF (100 ml), once for 5 min and once for 15 min. The resin was washed with DMF, methanol and DCM. This material was treated with isoamyl nitrite (1.79 ml, 12.30 mmols) and acetic acid (0.074 ml, 1.23 mmols) in anhydrous chloroform (70 ml) for 1 hr, then filtered and washed with DMF, methanol and DCM then finally air dried to give the title compound.